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Characterization and gene expression of transmissible Mycobacterium Tuberculosis strains in South Africa

Muller, Odelia (2008-03)

Thesis (MSc) -- Stellenbosch University, 2008

Thesis

ENGLISH ABSTRACT: The Mycobacterium tuberculosis Beijing strain family is a dominant strain family in most countries world wide, including South Africa. It has been suggested that this strain family has unique properties. These include the ability to evade the protective effect of Bacillus Calmette-Guérin vaccination, spread more readily and the more frequent acquisition of drug resistance. These properties might be the reasons for the Beijing strain’s successful transmission. Comparative genomics have suggested that strains from the Beijing family can be broadly grouped into typical and atypical strains according to the presence or absence of an IS6110 insertion in the NTF region in the genome of Mycobacterium tuberculosis. Phylogenetic analysis showed that these two groups originated from a common progenitor. However, the atypical Beijing strain has only rarely been identified. The atypical Beijing strains are also not frequently associated with drug resistance, is attenuated and therefore do not spread readily. In contrast, by applying molecular epidemiological techniques, this study showed that an atypical Beijing strain acquired drug resistance and was spreading amongst tuberculosis re-treatment patients in the Eastern Cape province of South Africa. Further molecular analysis showed that this strain had a high fitness cost mutation in the rpoB gene, conferring rifampicin resistance. This correlates with in vitro generated rpoB mutants. The human immune deficiency virus/tuberculosis co-infection was found to be a significant co-factor, which allowed the atypical Beijing strain to be transmitted. Therefore, the attenuated atypical Beijing strain can overcome its fitness cost in high human immune deficiency virus burdened communities and may cause ongoing transmission. This raises concern for the spread of all drug-resistant strains in vulnerable populations. By analysing a longitudinal reference database at the University of Stellenbosch, it has been observed that the strain dynamics within a strain family differs. There are large and small clusters in the Beijing strain family which is suggestive of more and less transmissible strains. Comparative proteomic analysis by 2-D gel electrophoresis identified 64 protein spots which were different between a large and small cluster in the Beijing strain family. Similarly, 59 protein spots were found different between the attenuated atypical Beijing strain and the typical large Beijing cluster. By comparing the atypical Beijing strain to the small Beijing cluster it was found that 132 protein spots were different between the two strains. These results strongly suggest that differential expression of certain genes is associated with differential transmission of different Beijing sub-lineages. The same may be true for other Mycobacterium tuberculosis strain families. It is likely that the bacterial genomic background play a more dominant role in the differential transmission of certain Mycobacterium tuberculosis strains, than host or programmatic related factors. A more comprehensive study, which involves the bacterium, host, and the tuberculosis control program, is needed to prove this assumption.